Neuromodulation of inflammation and endothelial function to treat elderly patients with systolic heart failure.

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Heart failure with reduced ejection fraction (HFrEF) is a major cause of morbidity and mortality in United States. Aging and HFrEF are unique in that they share common pathologies, such as autonomic imbalance (increased sympathetic and reduced parasympathetic tone), inflammation (termed “inflammaging”) and endothelial dysfunction. Aging is a major risk factor for adverse outcomes associated with HFrEF. Despite treatment, majority of HFrEF patients continue to experience reduced exercise capacity and poor quality of life (QoL). Recent studies have suggested that age-associated autonomic imbalance, inflammation and endothelial dysfunction may play a central role in the progression of HFrEF, supporting the notion that attenuating these abnormalities may help improve clinical outcomes in HFrEF. We have previously demonstrated that low level transcutaneous tragus stimulation (LLTS) improves autonomic imbalance and suppresses inflammation in patients with atrial fibrillation and diastolic dysfunction and improved endothelial dysfunction in patients with HFrEF. The overall objective of this proposal is to examine the effects of LLTS on exercise capacity and QoL in patients with HFrEF and simultaneously determine its impact on the core age-related pathologic axes, autonomic imbalance, inflammation and endothelial dysfunction. Our specific aims include: 1. To examine the medium-term effect of intermittent (1-hour daily for 3 months) LLTS on exercise capacity and QoL, relative to sham stimulation, in patients with HFrEF, 2. To determine the effects of medium- term LLTS on autonomic imbalance (assessed by heart rate variability) and inflammation in patients with HFrEF and 3. To determine the effects of medium-term LLTS on endothelial function in patients with HFrEF. The proposed proof-of-concept human feasibility study will provide the basis for using LLTS among larger HFrEF populations. This proposal intends to a) elucidate the effects of LLTS on age-related abnormalities (autonomic imbalance, inflammation and endothelial dysfunction) and progression of HFrEF outcomes (exercise capacity and QoL) and b) develop and further refine novel therapies, such as LLTS, to ameliorate the underlying age- associated derangements and clinical outcomes. In light of the increasing number of elderly patients who, despite treatment, continue to experience HFrEF symptoms, recognized is a key point of interest in this funding mechanism, an alternative novel approach such as LLTS has the potential to improve health outcomes in HFrEF. It is anticipated that these investigations will contribute to a broader understanding of age-associated autonomic imbalance, inflammation and endothelial dysfunction in HFrEF and how its inhibition can be used to provide therapeutic effects.